Small-molecule approaches to restore glycemic control in type 1 diabetes Beta-cell death, and the concomitant deficiency in insulin secretion, is a key feature of type 1 diabetes. Loss of glycemic control in type 1 diabetes represents the most direct target for clinical intervention. For decades, the standard of care for type 1 diabetes has been insulin injection. Current approaches to develop new treatments have prioritized islet transplantation and directed stem-cell differentiation, while many technological advances have focused on glucose detection and insulin delivery methods. However, a chemical intervention capable of restoring glycemic control would have enormous impact clinically, by enabling an in vivo pancreatic effect while avoiding the need for immunosuppression. In this Type 1 Diabetes Pathfinder proposal, I describe a chemical biology approach to 1) develop a suite of cell-based assays for high-throughput screening to identify small molecules that prevent cytokine-induced beta-cell death, and 2) use a novel high-throughput metabolic-profiling technology to assess nutrient dependence on pancreatic cell viability and function. Compounds identified in the first approach would serve as candidates for improvement of beta-cell function in cell culture and, ultimately, for therapeutic follow-up. The second approach will enable a metabolic network- dependent dissection of the differences between various pancreatic endocrine and exocrine cell types, and how nutrient metabolism affects beta-cell viability and function. The success of this project has the potential for enormous clinical impact on type 1 diabetes, by paving the way toward the development of novel drugs to prevent beta-cell death and thus restore glycemic control in patients; this project also represents one of the first large-scale efforts to screen for compounds with an impact on beta-cell biology.